{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T07:04:17Z","timestamp":1774940657763,"version":"3.50.1"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["HT9425-23-1-303 0146"],"award-info":[{"award-number":["HT9425-23-1-303 0146"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Snake venom activity exhibits evolutionary patterns within genera and varies according to ecological niche. By examining venoms from species inhabiting distinct environments, niche-specific functional differences can be uncovered.\n                    <jats:italic>Bothrops<\/jats:italic>\n                    , a diverse and medically important Neotropical pit viper genus, shows known clade-specific differences in coagulotoxicity. Here, we expanded this framework by assessing intra-clade variation in cellular activity across twelve\n                    <jats:italic>Bothrops<\/jats:italic>\n                    species using a high-content fluorescence assay that simultaneously measures ion channel responses and membrane cytotoxicity. Most venoms induced rapid membrane damage and cell lysis, whereas arboreal species lacked both activities, suggesting reduced selection for these activities. In contrast, the terrestrial\n                    <jats:italic>Bothrops mattogrossensis<\/jats:italic>\n                    and\n                    <jats:italic>Bothrops pauloensis,<\/jats:italic>\n                    which are sister species inhabiting the Pantanal wetlands and outskirts, respectively, displayed unique intracellular calcium-modulatory effects in the absence of membrane disruption. High throughput venomics revealed candidate toxin families underlying these calcium responses. Our findings demonstrate niche-specific diversification of venom bioactivity and highlight\n                    <jats:italic>Bothrops<\/jats:italic>\n                    venoms as promising sources of pharmacological agents.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1769550","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T05:32:59Z","timestamp":1774935179000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Bothrops venom variation drives niche-specific pharmacology through Ca2+ signalling and membrane damage"],"prefix":"10.3389","volume":"17","author":[{"given":"Lachlan A.","family":"Bourke","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland","place":["Brisbane, QLD, Australia"]},{"name":"School of the Environment, The University of Queensland","place":["Brisbane, QLD, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julien","family":"Slagboom","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute of Molecular and Life Sciences, Division of BioAnalytical Chemistry, Faculty of Science, Vrije Universiteit Amsterdam","place":["Amsterdam, Netherlands"]},{"name":"Centre for Analytical Sciences Amsterdam (CASA)","place":["Amsterdam, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A.","family":"Waller","sequence":"additional","affiliation":[{"name":"The Dr John and Anne Chong Laboratory for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. Gregory","family":"Neely","sequence":"additional","affiliation":[{"name":"The Dr John and Anne Chong Laboratory for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeroen","family":"Kool","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute of Molecular and Life Sciences, Division of BioAnalytical Chemistry, Faculty of Science, Vrije Universiteit Amsterdam","place":["Amsterdam, Netherlands"]},{"name":"Centre for Analytical Sciences Amsterdam (CASA)","place":["Amsterdam, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernanda C.","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland","place":["Brisbane, QLD, Australia"]},{"name":"Centre for Innovation in Pain and Health Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland","place":["Brisbane, QLD, Australia"]},{"name":"Centre for Motor Neuron Disease Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland","place":["Brisbane, QLD, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.toxicon.2014.02.018","article-title":"A lectin from Bothrops leucurus snake venom raises cytosolic calcium levels and promotes B16-F10 melanoma necrotic cell death via mitochondrial permeability transition","volume":"82","author":"Aranda-Souza","year":"2014","journal-title":"Toxicon"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2443","DOI":"10.1098\/rspb.2009.0048","article-title":"Coevolution of diet and prey-specific venom activity supports the role of selection in snake venom evolution","volume":"276","author":"Barlow","year":"2009","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/s42003-024-06019-6","article-title":"Tissue damaging toxins in snake venoms: mechanisms of action, pathophysiology and treatment strategies","volume":"7","author":"Bittenbinder","year":"2024","journal-title":"Commun. Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"297","DOI":"10.3390\/toxins14050297","article-title":"Clinical and evolutionary implications of dynamic coagulotoxicity divergences in bothrops (lancehead pit viper) venoms","volume":"14","author":"Bourke","year":"2022","journal-title":"Toxins (Basel)."},{"key":"B5","doi-asserted-by":"publisher","first-page":"107756","DOI":"10.1016\/j.toxicon.2024.107756","article-title":"Fangs and foliage: unearthing the haemotoxic secrets of cannabis-dwelling rattlesnakes","volume":"244","author":"Bourke","year":"2024","journal-title":"Toxicon"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15569543.2025.2510255","article-title":"Modulation of intracellular calcium signaling by American pit viper venoms: a systematic review","volume":"44","author":"Bourke","year":"2025","journal-title":"Toxin Rev."},{"key":"B7","volume-title":"The venomous reptiles of the Western hemisphere","author":"Campbell","year":"2004"},{"key":"B8","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1124\/mol.115.098178","article-title":"Identification and characterization of ProTx-III [\u03bc-TRTX-Tp1a], a new voltage-gated sodium channel inhibitor from venom of the tarantula Thrixopelma pruriens","volume":"88","author":"Cardoso","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1097\/j.pain.0000000000002041","article-title":"A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome","volume":"162","author":"Cardoso","year":"2021","journal-title":"PAIN"},{"key":"B10","doi-asserted-by":"crossref","DOI":"10.3390\/ijms232113077","article-title":"The deadly toxin arsenal of the tree-dwelling Australian funnel-web spiders","volume-title":"International journal of molecular sciences","author":"Cardoso","year":"2022"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1069764","DOI":"10.3389\/fmolb.2023.1069764","article-title":"Holistic profiling of the venom from the Brazilian wandering spider Phoneutria nigriventer by combining high-throughput ion channel screens with venomics","volume":"10","author":"Cardoso","year":"2023","journal-title":"Front. Mol. Biosci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1111\/cla.12522","article-title":"Total-evidence phylogeny and evolutionary morphology of new world pitvipers (serpentes: viperidae: crotalinae)","volume":"39","author":"Carrasco","year":"2023","journal-title":"Cladistics"},{"key":"B13","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/j.tips.2020.05.006","article-title":"Causes and consequences of snake venom variation","volume":"41","author":"Casewell","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"6165","DOI":"10.1007\/s00253-016-7610-9","article-title":"Snake venom toxins: toxicity and medicinal applications","volume":"100","author":"Chan","year":"2016","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s40409-015-0011-1","article-title":"Epidemiology of envenomations by terrestrial venomous animals in Brazil based on case reporting: from obvious facts to contingencies","volume":"21","author":"Chippaux","year":"2015","journal-title":"J. Venom. Anim. Toxins Incl. Trop. Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1007\/s00018-009-9053-2","article-title":"Calcium imaging of muscle cells treated with snake myotoxins reveals toxin synergism and presence of acceptors","volume":"66","author":"Cintra-Francischinelli","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"612649","DOI":"10.1155\/2013\/612649","article-title":"Biochemical, pharmacological, and structural characterization of new basic PLA2 Bbil-TX from bothriopsis bilineata snake venom","volume":"2013","author":"Corasolla Carregari","year":"2013","journal-title":"BioMed Res. Int."},{"key":"B18","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1111\/tmi.13207","article-title":"Snakebite accidents in Rio Grande do Norte state, Brazil: epidemiology, health management and influence of the environmental scenario","volume":"24","author":"Costa","year":"2019","journal-title":"Trop. Med. Int. Health"},{"key":"B19","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1590\/1809-4392201901561","article-title":"Epidemiological and clinical aspects of snakebites in the upper jurua river region, Western Brazilian Amazonia","volume":"50","author":"da Silva","year":"2020","journal-title":"Acta Amaz."},{"key":"B20","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/379537a0","article-title":"Diet and snake venom evolution","volume":"379","author":"Daltry","year":"1996","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1093\/trstmh\/tru038","article-title":"Epidemiology of snakebite and use of antivenom in Argentina","volume":"108","author":"Dolab","year":"2014","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"B22","doi-asserted-by":"publisher","first-page":"218","DOI":"10.3389\/fevo.2019.00218","article-title":"Multifunctional toxins in snake venoms and therapeutic implications: from pain to hemorrhage and necrosis","volume":"7","author":"Ferraz","year":"2019","journal-title":"Front. Ecol. Evol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.toxicon.2013.03.006","article-title":"Pharmacological study of a new Asp49 phospholipase A2 (Bbil-TX) isolated from bothriopsis bilineata smargadina (forest viper) venom in vertebrate neuromuscular preparations","volume":"69","author":"Floriano","year":"2013","journal-title":"Toxicon"},{"key":"B24","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.toxicon.2015.01.001","article-title":"The neuromuscular activity of bothriopsis bilineata smaragdina (forest viper) venom and its toxin Bbil-TX (Asp49 phospholipase A2) on isolated mouse nerve-muscle preparations","volume":"96","author":"Floriano","year":"2015","journal-title":"Toxicon"},{"key":"B25","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.toxicon.2015.09.007","article-title":"Partial in vitro analysis of toxic and antigenic activities of eleven Peruvian pitviper snake venoms","volume":"108","author":"Guerra-Duarte","year":"2015","journal-title":"Toxicon"},{"key":"B26","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1016\/j.toxicon.2009.01.038","article-title":"Experimental pathology of local tissue damage induced by Bothrops asper snake venom","volume":"54","author":"Guti\u00e9rrez","year":"2009","journal-title":"Toxicon"},{"key":"B27","doi-asserted-by":"publisher","first-page":"17063","DOI":"10.1038\/nrdp.2017.63","article-title":"Snakebite envenoming","volume":"3","author":"Guti\u00e9rrez","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e2015579118","DOI":"10.1073\/pnas.2015579118","article-title":"Phylogenetically diverse diets favor more complex venoms in North American pitvipers","volume":"118","author":"Holding","year":"2021","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"309","DOI":"10.3390\/toxins8110309","article-title":"Rapid radiations and the race to redundancy: an investigation of the evolution of Australian elapid snake venoms","volume":"8","author":"Jackson","year":"2016","journal-title":"Toxins"},{"key":"B30","doi-asserted-by":"publisher","first-page":"100184","DOI":"10.1016\/j.toxcx.2024.100184","article-title":"High-content fluorescence bioassay investigates pore formation, ion channel modulation and cell membrane lysis induced by venoms","volume":"21","author":"Kramer","year":"2024","journal-title":"Toxicon X"},{"key":"B31","doi-asserted-by":"publisher","first-page":"107024","DOI":"10.1016\/j.toxicon.2023.107024","article-title":"Lys49 myotoxins, secreted phospholipase A2-like proteins of viperid venoms: a comprehensive review","volume":"224","author":"Lomonte","year":"2023","journal-title":"Toxicon"},{"key":"B32","article-title":"Diet breadth mediates the prey specificity of venom potency in snakes","volume-title":"Toxins","author":"Lyons","year":"2020"},{"key":"B33","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.toxicon.2020.08.016","article-title":"Edema, hyperalgesia and myonecrosis induced by Brazilian bothropic venoms: overview of the last decade","volume":"187","author":"Mamede","year":"2020","journal-title":"Toxicon"},{"key":"B34","doi-asserted-by":"publisher","first-page":"107547","DOI":"10.1016\/j.toxicon.2023.107547","article-title":"Three snake venoms from bothrops genus induced apoptosis and cell cycle arrest in K562 human leukemic cell line","volume":"238","author":"Marinho","year":"2024","journal-title":"Toxicon"},{"key":"B35","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1017\/S0952836901001030","article-title":"Diversity and evolution of macrohabitat use, body size and morphology in a monophyletic group of neotropical pitvipers (bothrops)","volume":"254","author":"Martins","year":"2001","journal-title":"J. Zoology"},{"key":"B36","article-title":"Ecological and phylogenetic correlates of feeding habits in neotropical pitvipers of the genus bothrops","volume-title":"Biology of the vipers","author":"Martins","year":"2002"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2253","DOI":"10.1111\/brv.13120","article-title":"Prey specificity of predatory venoms","volume":"99","author":"Mich\u00e1lek","year":"2024","journal-title":"Biol. Rev."},{"key":"B38","doi-asserted-by":"publisher","first-page":"100037","DOI":"10.1016\/j.toxcx.2020.100037","article-title":"Bothrops atrox, the Most important snake involved in human envenomings in the Amazon: how venomics contributes to the knowledge of snake biology and clinical toxinology","volume":"6","author":"Monteiro","year":"2020","journal-title":"Toxicon X"},{"key":"B39","doi-asserted-by":"publisher","first-page":"106983","DOI":"10.1016\/j.toxicon.2022.106983","article-title":"Half a century of research on Bothrops asper venom variation: biological and biomedical implications","volume":"221","author":"Mora-Obando","year":"2023","journal-title":"Toxicon"},{"key":"B40","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.2994\/Sajh-D-19-00120.1","article-title":"Atlas of Brazilian snakes: verified point-locality maps to mitigate the wallacean shortfall in a megadiverse snake fauna","volume":"14","author":"Nogueira","year":"2019","journal-title":"S. Am. J. Herpetology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.toxicon.2009.07.001","article-title":"Epidemiological, clinical and therapeutic aspects of Bothrops asper bites","volume":"54","author":"Otero-Patino","year":"2009","journal-title":"Toxicon"},{"key":"B42","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1007\/s40475-020-00203-4","article-title":"Bothrops snakebite envenomings in the amazon region","volume":"7","author":"Resiere","year":"2020","journal-title":"Curr. Trop. Med. Rep."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1016\/0041-0101(95)00089-5","article-title":"No role for enzymatic activity or dantrolene-sensitive Ca2+ stores in the muscular effects of bothropstoxin, a Lys49 phospholipase A2 myotoxin","volume":"33","author":"Rodrigues-Simioni","year":"1995","journal-title":"Toxicon"},{"key":"B44","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.toxicon.2011.05.002","article-title":"Presynaptic action of bothriopsis bilineata smargadina (forest viper) venom in vitro","volume":"58","author":"Rodrigues-Simioni","year":"2011","journal-title":"Toxicon"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4172\/2161-0495.1000197","article-title":"Biochemical characterization of a PLA2 btae TX-I isolated from bothriopsis Taeniata snake venom: a pharmacological and morphological study","volume":"4","author":"Romero-Vargas","year":"2014","journal-title":"J. Clin. Toxicol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/S0014-5793(00)01803-2","article-title":"Interaction of viper venom serine peptidases with thrombin receptors on human platelets","volume":"477","author":"Santos","year":"2000","journal-title":"FEBS Lett."},{"key":"B47","article-title":"Diversity begets diversity when diet drives snake venom evolution, but evenness rather than richness is what counts","volume-title":"Toxins","author":"Schaeffer","year":"2023"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e0007802","DOI":"10.1371\/journal.pntd.0007802","article-title":"High throughput screening and identification of coagulopathic snake venom proteins and peptides using nanofractionation and proteomics approaches","volume":"14","author":"Slagboom","year":"2020","journal-title":"PLOS Neglected Trop. Dis."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1021\/acs.jproteome.2c00780","article-title":"High-throughput venomics","volume":"22","author":"Slagboom","year":"2023","journal-title":"J. Proteome Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/s12915-023-01626-x","article-title":"Snakes on a plain: biotic and abiotic factors determine venom compositional variation in a wide-ranging generalist rattlesnake","volume":"21","author":"Smith","year":"2023","journal-title":"BMC Biol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.jprot.2017.03.003","article-title":"Functional proteomic analyses of Bothrops atrox venom reveals phenotypes associated with habitat variation in the amazon","volume":"159","author":"Sousa","year":"2017","journal-title":"J. Proteomics"},{"key":"B52","doi-asserted-by":"publisher","first-page":"411","DOI":"10.3390\/toxins10100411","article-title":"Coagulotoxicity of bothrops (lancehead pit-vipers) venoms from Brazil: differential biochemistry and antivenom efficacy resulting from prey-driven venom variation","volume":"10","author":"Sousa","year":"2018","journal-title":"Toxins"},{"key":"B53","doi-asserted-by":"publisher","first-page":"108818","DOI":"10.1016\/j.cbpc.2020.108818","article-title":"Varespladib (LY315920) neutralises phospholipase A(2) mediated prothrombinase-inhibition induced by bitis snake venoms","volume":"236","author":"Youngman","year":"2020","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"20182735","DOI":"10.1098\/rspb.2018.2735","article-title":"When one phenotype is not enough: divergent evolutionary trajectories govern venom variation in a widespread rattlesnake species","volume":"286","author":"Zancolli","year":"2019","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.toxlet.2020.05.014","article-title":"Anticoagulant activity of Black snake (elapidae: pseudechis) venoms: mechanisms, potency, and antivenom efficacy","volume":"330","author":"Zdenek","year":"2020","journal-title":"Toxicol. Lett."},{"key":"B56","doi-asserted-by":"publisher","first-page":"E2524","DOI":"10.1073\/pnas.1615484114","article-title":"Lys49 myotoxin from the Brazilian lancehead pit viper elicits pain through regulated ATP release","volume":"114","author":"Zhang","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1769550\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T05:33:01Z","timestamp":1774935181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1769550\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":56,"alternative-id":["10.3389\/fphar.2026.1769550"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1769550","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]},"article-number":"1769550"}}